Local administration of non-cellular mediators (e.g., lymphokines of cell-mediated immunity (CMI) produces reactions resembling (CMI) cell-mediated challenge responses in normal skin and can result in regressions of various types of tumors in animals and man. Preparations with lymphokine activities (LK) were obtained from primary cultures of peripheral normal human lymphocytes and established lines of human diploid lymphocytes of B and T-cell origin. Fraction of LK obtained by ammonium sulfate precipitation have been included in these studies. The effects of LK on normal skin and accessible tumors are being correlated with defects in immunocompetence. These studies indicate a relationship of the local anti-tumor effects of the CMI reactions to the actions of non-cellular and cellular components of CMI. Concurrent studies are being carried out on the lymphocyte responses of patients with advanced cancer. The effects of sera of these patients on normal lymphocytes, monocytes, and granulocytes are also being investigated. Current studies indicate that some of the immune defects in patients with advanced cancers can be reversed by the administration of LK. Recent findings have shown that concurrent administration of antigens and of some cytotoxic agents (locally or systemically in low doses) result in augmentation, rather than inhibition, of CMI challenge responses in normal skin and consequent local anti-tumor effect. We further found augmentation of the corresponding effects of LK by cytotoxic agents in patients with advanced cancer with and without immune defects. This appears to be in agreement with recent reports that low levels of cytotoxic agents inhibit the actions of suppressor T lymphocytes in vitro and in animals. Studies were carried out in patients with severe genetic diseases with and without associated intractable multiple skin cancer syndromes as well as in patients with other advanced malignant diseases involving the skin and subcutaneous tissues. Early indications indicate the possible therapeutic significance of combining cytotoxic agents with CMI challenge responses induced by antigens and/or LK administration.